PROJECT SUMMARY The inhibitory thalamic reticular nucleus (TRN) envelops the dorsal thalamus. The TRN is poised to gate thalamo- cortical signals through two-way connections with the dorsal thalamus, and as the recipient of unidirectional pathways from the entire cerebral cortex. We previously discovered that three interconnected regions in primates, the mediodorsal thalamic nucleus (MD), specific prefrontal cortices (PFC) and the amygdala innervate the frontal, as well as the sensory TRN sectors. This evidence suggests prefrontal control of attention to help select salient stimuli for flexible, goal directed behavior. These developments highlight the need to systematically evaluate the as-yet unknown microcircuitry linking TRN with dorsal thalamic nuclei, which give rise to laminar- specific pathways to cortex. These studies are predicated on primate specializations that may underlie normal and pathologic function through thalamus and cortex in humans. Our working hypothesis is that neurochemically-distinct inhibitory TRN neurons have specific synaptic interactions within TRN. In addition, distinct inhibitory TRN neurons have specialized connections with ?core? thalamic neurons that focally drive activity in the middle cortical layers, and ?matrix? thalamic neurons that broadly innervate the upper cortical layers. Experiments are designed to test this hypothesis by systematic study of: (1) the molecular and synaptic organization of neurochemically-distinct TRN neurons within TRN sectors; (2) pathways to TRN from: a model sensory thalamic nucleus, the visual lateral geniculate, which is connected with the visual cortex; and a model high-order thalamic nucleus, the MD, which is connected with PFC and the amygdala; (3) TRN pathways directed to each of these dorsal thalamic nuclei; (4) and use of the rich database obtained on excitatory and inhibitory circuits to simulate normal function within the TRN and dorsal thalamus, and disruption in disease. Identical high-resolution methods will be used to study pathway interactions in rhesus monkeys and humans. Excitatory and inhibitory pathways will be labeled using molecular, cellular and synaptic features that differentiate bidirectional circuits of TRN with dorsal thalamic nuclei to reliably separate them from other pathways. Quantitative analyses will be based on data from correlated confocal and electron microscopy, and 3D-reconstruction of pathways and synapses at multiple scales of resolution. Hypotheses about pathway interactions are based on a theoretical framework on the organization of corticothalamic networks and the significant expansion and specialization of TRN in parallel with the dorsal thalamus and cortex in primates. Findings from these studies will provide the circuit basis for the role of TRN and the thalamocortical systems in attentional modulation for sensory, cognitive and emotional processes and their disruption in sleep disorders and attention deficits in schizophrenia and autism.